Phenyl-guanidine derivatives

Abstract

Provided herein are phenyl-guanidine derivatives for the inhibition of Rac1 which blocks its interaction with guanosine exchange factors (GEFs) belonging to the DBL family as agents for the treatment of aggressive and/or resistant tumors, as well as pharmaceutical compositions comprising them, their use in therapy and processes for their preparation.

The invention claimed is: 
     
       1. A method for treating a cancer mediated by Rho-GTPase cell proteins in a human which comprises administering to said human an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof, or any of its stereoisomeric forms or a mixture thereof wherein: 
         R 1  is CF 3  and R 1 ′ is H; 
         wherein A is selected from: 
         A is a radical selected from linear or branched (C1-C6)alkyl or one of the known carbocyclic or heterocyclic ring systems with 1-2 rings, wherein each of the rings forming the ring system:
 has 5-7 members, each member independently selected from C, N, O, S, CH, CH 2 , NH; and 
 is saturated, partially unsaturated or aromatic; 
 wherein A is substituted by one or more radicals selected from the group consisting of H, halogen, nitro, cyano, linear or branched (C 1 -C 6 )alkyl, halo-(C 1 -C 6 )alkyl, linear or branched (C 2 -C 6 )alkenyl, —OR 2 , —COR 2 , —COOR 2 , —OC(O)R 2 , —C(O)NR 3 R 4 , —NR 3 R 4 , —R 5 NHR 6 , —SR 2 , —SO—R 2 , —SO 2 —R 2 , and —SO 2 NR 3 R 4 ; 
 
         wherein
 each R 2  independently represents H or linear or branched (C 1 -C 4 )alkyl, 
 each R 3  independently represents H or linear or branched (C 1 -C 4 )alkyl, 
 each R 4  independently represents H, linear or branched (C 1 -C 6 )alkyl, phenyl, pyridine or quinoline; wherein the phenyl, pyridine and quinoline ring system is substituted by one or more radical selected from H, linear or branched (C 1 -C 4 )alkyl, and NH 2 ; 
 R 5  and R 6  are independently selected from H, linear or branched (C 1 -C 4 )alkyl, together with pharmaceutical excipients or carriers. 
 
       
     
     
       2. The method according to  claim 1 , wherein A is a ring system selected from 
       
         
           
           
               
               
           
         
         wherein the wavy line indicates the point of attachment of the ring to the adjacent nitrogen, and wherein A is substituted as defined in  claim 1 . 
       
     
     
       3. The method according to  claim 2 , wherein A is a ring system selected from 
       
         
           
           
               
               
           
         
         wherein the wavy line indicates the point of attachment of the ring to the adjacent nitrogen; and wherein A is substituted by one or more radicals as defined in  claim 1 . 
       
     
     
       4. The method according to  claim 3 , wherein the ring system of A is substituted by one or more radicals selected from the group consisting of H, F, Cl, Br, I, nitro, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, —CF 3 , —CH 2 CF 3 , linear or branched (C 2 -C 6 )alkenyl, —OH, —CH 3 , —OCH 2 CH 3 , —COH, —COCH 3 , —COOH, —COOCH 3 , —COOCH 2 CH 3 , —OC(O)H, —OC(O)CH 3 , —C(O)NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 NHCH 3 , —SH 2 , —SO—CH 3 , —SO 2 —CH 3 , —SO 2 NH 2 , —SO 2 NHCH 3 , —SO 2 NHCH 2 CH 3 , —SO 2 N(CH 3 ) 2 , —SO 2 N(CH 2 CH 3 ) 2 , —SO 2 N(CH 2 CH 2 CH 3 ) 2 , —SO 2 N(CH 2 CH 2 CH 2 CH 3 ) 2  and —SO 2 N(CH 2 CH 2 (CH 3 ) 2 ) 2 . 
     
     
       5. The method according to  claim 1 , wherein the compound is of formula Ia: 
       
         
           
           
               
               
           
         
         or a salt thereof, or any of its stereoisomeric forms or a mixture thereof; 
         wherein R 1  is CF 3  and R 1 ′ is H. 
       
     
     
       6. The method according to  claim 5 , wherein A is a radical of one of the known heterocyclic ring systems with 1-2 rings,
 wherein each of the rings forming the ring system
 has 5-7 members, each member independently selected from C, N, O, S, CH, CH 2 , NH; 
 is saturated, partially unsaturated or aromatic; 
 
 wherein A is substituted by one or more radical selected from the group consisting of H, F, Br, I, nitro, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, —CF 3 , —CH 2 CF 3 , linear or branched (C 2 -C 6 )alkenyl, —OH, —OCH 3 , —OCH 2 CH 3 , —COH, —COCH 3 , —COOH, —COOCH 3 , —COOCH 2 CH 3 , —OC(O)H, —OC(O)CH 3 , —C(O)NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 NHCH 3 , —SH 2 , —SO—CH 3 , —SO 2 —CH 3 , —SO 2 NH 2 , —SO 2 NHCH 3 , —SO 2 NHCH 2 CH 3 , —SO 2 N(CH 3 ) 2 , —SO 2 N(CH 2 CH 3 ) 2 , —SO 2 N(CH 2 CH 2 CH 3 ) 2 , —SO 2 N(CH 2 CH 2 CH 2 CH 3 ) 2  and —SO 2 N(CH 2 CH 2 (CH 3 ) 2 ) 2 . 
 
     
     
       7. The method according to  claim 5 , wherein A is a phenyl radical substituted by one or more radicals selected from the group consisting of H, F, Cl, Br, I, nitro, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, —CF 3 , —CH 2 CF 3 , linear or branched (C 2 -C 6 )alkenyl, —OH, —OCH 3 , —OCH 2 CH 3 , —COH, —OCH 3 , —COOH, —COOCH 3 , —COOCH 2 CH 3 , —OC(O)H, —OC(O)CH 3 , —(O)NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 NHCH 3 , —SH 2 , —SO—CH 3 , —SO 2 —CH 3 , —SO 2 NH 2 , —SO 2 NHCH 3 , —SO 2 NHCH 2 CH 3 , —SO 2 N(CH 3 ) 2 , —SO 2 N(CH 2 CH 3 ) 2 , —SO 2 N(CH 2 CH 2 CH 3 ) 2 , —SO 2 N(CH 2 CH 2 CH 2 CH 3 ) 2  and —SO 2 N(CH 2 CH 2 (CH 3 ) 2 ) 2 . 
     
     
       8. The method according to  claim 1 , wherein the compound is selected from:
 N-pyrimidin-2-yl-N′-[2-(trifluoromethyl)phenyl]guanidine (1); 
 N-(4-ethyl-6-methylpyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (2); 
 N-(4-methyl-6-propylpyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (3); 
 N-(4-isopropyl-6-methylpyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (4); 
 N-(4-butyl-6-methylpyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (5); 
 N-(4-tert-butyl-6-methylpyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (6); 
 N-(4,6-diaminopyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (7); 
 N-(4,6-dichloropyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (8); 
 N-(4,6-difluoropyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (9); 
 N-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-N′-[2-(trifluoromethyl)phenyl]guanidine (10); 
 N-(4-cyano-6-methylpyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (11); 
 N-(5-methylpyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (12); 
 N-(4-chloro-6-methylpyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (13); 
 N-(4-fluoro-6-methylpyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (14); 
 N-(4-fluoropyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (15); 
 N-(5-fluoropyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (16); 
 N-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-N′-[2-(trifluoromethyl)phenyl]guanidine (17); 
 N-(4,6-dicyanopyrimidin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (18); 
 N-pyridin-2-yl-N′-[2-(trifluoromethyl)phenyl]guanidine (19); 
 N-pyridin-3-yl-N′-[2-(trifluoromethyl)phenyl]guanidine (20); 
 N-pyridin-4-yl-N′-[2-(trifluoromethyl)phenyl]guanidine (21); 
 N-pyrimidin-4-yl-N′-[2-(trifluoromethyl)phenyl]guanidine (22); 
 N-pyrimidin-5-yl-N-[2-(trifluoromethyl)phenyl]guanidine (23); 
 N-(4,6-dimethylpyridin-2-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (24); 
 N-(3,5-dimethylphenyl)-N-[2-(trifluoromethyl)phenyl]guanidine (25); 
 N-(2,6-dimethylpyridin-4-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (26); 
 N-phenyl-N′-[2-(trifluoromethyl)phenyl]guanidine (27); 
 2-[(imino{[2-(trifluoromethyl)phenyl]amino}methyl)amino]-N,N-dimethylbenzenesulfonamide (28); 
 2-[(imino{[2-(trifluoromethyl)phenyl]amino}methyl)amino]-N,N-diethylbenzenesulfonamide (29); 
 2-[(imino{[2-(trifluoromethyl)phenyl]amino}methyl)amino]-N,N-dipropylbenzenesulfonamide (30); 
 2-[(imino{[2-(trifluoromethyl)phenyl]amino}methyl)amino]-N,N-dibutylbenzenesulfonamide (31); 
 3-[(imino{[2-(trifluoromethyl)phenyl]amino}methyl)amino]-N,N-dimethylbenzenesulfonamide (32); 
 3-[(imino{[2-(trifluoromethyl)phenyl]amino}methyl)amino]-N,N-diethylbenzenesulfonamide (33); 
 3-[(imino{[2-(trifluoromethyl)phenyl]amino}methyl)amino]-N,N-dipropylbenzenesulfonamide (34); 
 3-[(imino{[2-(trifluoromethyl)phenyl]amino}methyl)amino]-N,N-dibutylbenzenesulfonamide (35); 
 4-[(imino{[2-(trifluoromethyl)phenyl]amino}methyl)amino]-N,N-dimethylbenzenesulfonamide (36); 
 4-[(imino{[2-(trifluoromethyl)phenyl]amino}methyl)amino]-N,N-diethylbenzenesulfonamide (37); 
 4-[(imino{[2-(trifluoromethyl)phenyl]amino}methyl)amino]-N,N-dipropylbenzenesulfonamide (38); 
 4-[(imino{[2-(trifluoromethyl)phenyl]amino}methyl)amino]-N,N-dibuthylbenzenesulfonamide (39); 
 N-(2-nitrophenyl)-N′-[2-(trifluoromethyl)phenyl]guanidine (40); 
 N-(3-nitrophenyl)-N′-[2-(trifluoromethyl)phenyl]guanidine (41); 
 N-(4-nitrophenyl)-N′-[2-(trifluoromethyl)phenyl]guanidine (42); 
 N-2-thienyl-N′-[2-(trifluoromethyl)phenyl]guanidine (43); 
 N-3-thienyl-N′-[2-(trifluoromethyl)phenyl]guanidine (44); 
 N-1H-pyrrol-2-yl-N′-[2-(trifluoromethyl)phenyl]guanidine (45); 
 N-1H-pyrrol-3-yl-N′-[2-(trifluoromethyl)phenyl]guanidine (46); 
 N-2-furyl-N′-[2-(trifluoromethyl)phenyl]guanidine (47); 
 N-3-furyl-N′-[2-(trifluoromethyl)phenyl]guanidine (48); 
 N-1,3-oxazol-2-yl-N′-[2-(trifluoromethyl)phenyl]guanidine (49); 
 N-1,3-thiazol-2-yl-N′-[2-(trifluoromethyl)phenyl]guanidine (50); 
 N-1H-imidazol-2-yl-N′-[2-(trifluoromethyl)phenyl]guanidine (51); 
 N-isoxazol-5-yl-N′-[2-(trifluoromethyl)phenyl]guanidine (52); 
 N-1H-benzimidazol-2-yl-N′-[2-(trifluoromethyl)phenyl]guanidine (53); 
 N-(3,4-dimethylisoxazol-5-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (54); 
 1-(4-(4-amino-2-methylquinolin-7-ylamino)pyrimidin-2-yl)-3-(2-(trifluoromethyl)phenyl)guanidine (57); 
 N-(4-amino-2-methylquinolin-7-yl)-N′-[2-(trifluoromethyl)phenyl]guanidine (58); 
 N-quinolin-7-yl-N′-[2-(trifluoromethyl)phenyl]guanidine (59); 
 N-methyl-N′-[2-(trifluoromethyl)phenyl]guanidine (60); 
 N-ethyl-N′-[2-(trifluoromethyl)phenyl]guanidine (61); 
 N-propyl-N′-[2-(trifluoromethyl)phenyl]guanidine (62); 
 N-buthyl-N′-[2-(trifluoromethyl)phenyl]guanidine (63); 
 N-(2-methylphenyl)-N′-[2-(trifluoromethyl)phenyl]guanidine (64); and 
 N-[4,6-bis(methyl)pyrimidin-2-yl]-N′-[2-(trifluoromethyl)phenyl]guanidine (65). 
 
     
     
       9. The method according to  claim 1 , wherein the compound is selected from:
 N-[4,6-bis(methyl)pyrimidin-2-yl]-N′-[2-(trifluoromethyl)phenyl]guanidine (65), 
 N-(3,5-dimethylphenyl)-N′-[2-(trifluoromethyl)phenyl]guanidine (25), 
 N-phenyl-N′-[2-(trifluoromethyl)phenyl]guanidine (27), 
 N-(3-nitrophenyl)-N′-[2-(trifluoromethyl)phenyl]guanidine (41), 
 N-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-N′-[2-(trifluoromethyl)phenyl]guanidine (10), and 
 N-(2-methylphenyl)-N′-[2-(trifluoromethyl)phenyl]guanidine (64). 
 
     
     
       10. The method according to  claim 1 , wherein the cancer mediated by Rho-GTPase cell proteins is a proliferative disorder selected from the group consisting of precancerosis; dysplasia; metaplasia; carcinomas of the gastrointestinal or colorectal tract, liver, pancreas, kidney, bladder, prostate, endometrium, ovary, testes, melanoma, dysplastic oral mucosa, invasive oral cancers, small cell and non-small cell lung carcinomas, hormone-dependent breast cancers, hormone-independent breast cancers, transitional and squamous cell cancers, neurological malignancies including neuroblastoma, gliomas, glioblastoma, astrocytomas, osteosarcomas, soft tissue sarcomas, hemangioamas, endocrinological tumors, hematologic neoplasias including leukemias, lymphomas, and other myeloproliferative and lymphoproliferative diseases, carcinomas in situ, hyperplastic lesions, adenomas, fibromas, histiocytosis, chronic inflammatory proliferative diseases, vascular proliferative diseases, virus-induced proliferative diseases, and skin diseases characterized by hyperproliferation of keratinocytes and/or T cells. 
     
     
       11. The method according to any  claim 1 , wherein the method comprises administering to a subject simultaneously, sequentially or separately a compound of formula I and
 i) one or more anticancer agents; 
 ii) radiotherapy; 
 iii) conventional surgery; 
 iv) or mixtures thereof. 
 
     
     
       12. A compound of formula (II) 
       
         
           
           
               
               
           
         
         or a salt thereof, or any of its stereoisomeric forms or a mixture thereof wherein: 
         A is a radical of one of the known carbocyclic or heterocyclic ring systems with 1-2 rings, 
         wherein each of the rings forming the ring system
 has 5-7 members, each member independently selected from C, N, O, S, CH, CH 2 , NH; 
 is saturated, partially unsaturated or aromatic; 
 
         wherein A is substituted by one or more radicals selected from the group consisting of H, F, Cl, Br, I, nitro, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, linear or branched (C 2 -C 6 )alkenyl, —OH, —OCH 3 , —OCH 2 CH 3 , —COH, —COCH 3 , —COOH, —COOCH 3 , —COOCH 2 CH 3 , —OC(O)H, —OC(O)CH 3 , —C(O)NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 NHCH 3 , —SH 2 , —SO—CH 3 , —SO 2 —CH 3 , —SO 2 NH 2 , —SO 2 NHCH 3 , —SO 2 NHCH 2 CH 3 , —SO 2 N(CH 3 ) 2 , —SO 2 N(CH 2 CH 3 ) 2 , —SO 2 N(CH 2 CH 2 CH 3 ) 2 , —SO 2 N(CH 2 CH 2 CH 2 CH 3 ) 2  and —SO 2 N(CH 2 CH 2 (CH 3 ) 2 ) 2 ; 
         with the proviso that the compound is other than N-(4-methyl-6-hydroxy-pyrimidin-2-yl)-N′-(2-trifluoromethylphenyl)guanidine, N-[4,6-bis(methyl)pyrimidin-2-yl]-N′-[2-(trifluoromethyl)phenyl]guanidine or N-[(4-methyl)pyrimidin-2-yl]-N′-[2-(trifluoromethyl)phenyl]guanidine. 
       
     
     
       13. The compound according to  claim 12 , wherein A is a phenyl radical substituted by one or more radicals selected from the group consisting of H, F, Cl, Br, I, nitro, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, linear or branched (C 2 -C 6 )alkenyl,
 —OH, —OCH 3 , —OCH 2 CH 3 , —COH, —COCH 3 , —COOH, —COOCH 3 , —COOCH 2 CH 3 , —OC(O)H, —OC(O)CH 3 , —C(O)NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 NHCH 3 , —SH 2 , —SO—CH 3 , —SO 2 —CH 3 , —SO 2 NH 2 , —SO 2 NHCH 3 , —SO 2 NHCH 2 CH 3 , —SO 2 N(CH 3 ) 2 , —SO 2 N(CH 2 CH 3 ) 2 , —SO 2 N(CH 2 CH 2 CH 3 ) 2 , —SO 2 N(CH 2 CH 2 CH 2 CH 3 ) 2  and —SO 2 N(CH 2 CH 2 (CH 3 ) 2 ) 2 . 
 
     
     
       14. The compound according to  claim 12 , wherein A is a heterocyclic ring systems with 1-2 rings, wherein each of the rings forming the ring system
 has 5-7 members, each member independently selected from C, N, O, S, CH, CH 2 , NH; 
 is saturated, partially unsaturated or aromatic; 
 
       wherein A is substituted by one or more radicals selected from the group consisting of H, F, Cl, Br, I, nitro, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, linear or branched (C 2 -C 6 )alkenyl, —OH, —OCH 3 , —OCH 2 CH 3 , —COH, —COCH 3 , —COOH, —COOCH 3 , —COOCH 2 CH 3 , —OC(O)H, —OC(O)CH 3 , —C(O)NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 NHCH 3 , —SH 2 , —SO—CH 3 , —SO 2 —CH 3 , —SO 2 NH 2 , —SO 2 NHCH 3 , —SO 2 NHCH 2 CH 3 , —SO 2 N(CH 3 ) 2 , —SO 2 N(CH 2 CH 3 ) 2 , —SO 2 N(CH 2 CH 2 CH 3 ) 2 , —SO 2 N(CH 2 CH 2 CH 2 CH 3 ) 2  and —SO 2 N(CH 2 CH 2 (CH 3 ) 2 ) 2 ; 
       with the proviso that the compound is other than N-(4-methyl-6-hydroxy-pyrimidin-2-yl)-N′-(2-trifluoromethylphenyl)guanidine, N-[4,6-bis(methyl)pyrimidin-2-yl]-N′-[2-(trifluoromethyl)phenyl]guanidine or N-[(4-methyl)pyrimidin-2-yl]-N′-[2-(trifluoromethyl)phenyl]guanidine. 
     
     
       15. A pharmaceutical composition comprising at least one compound of  claim 12  and one or more pharmaceutically acceptable excipients or carriers. 
     
     
       16. The pharmaceutical composition according to  claim 15 , which further comprises another therapeutically active substance. 
     
     
       17. A process for preparing the compound of  claim 1 , which comprises reacting a compound of formula (III) with a compound of formula (IV):